Tyler Campbell was a football player, and a good one at that. He was strong, athletic, and instinctive, much like his father, legendary running back and hall of famer Earl Campbell. With plans to follow in his father’s footsteps to gridiron glory, Tyler awoke one morning while preparing for the NFL draft to a startling revelation – he was unable to move his arms and legs.
An estimated 250,000 to 350,000 Americans, including Tyler, suffer from multiple sclerosis, or MS. MS is an autoimmune disease in which destructive inflammation in the brain and spinal cord disrupts communication between the central nervous system and the rest of the body, often causing paralysis.
Inflammation, or the immune system’s natural response to injury or infection, falls into the category of “Dr. Jekyll and Mr. Hyde” biology. On one hand, inflammation is a crucial defense mechanism that ensures our survival. But, as in the case of Tyler Campbell, our immune system has the potential to spiral out of control and damage vital organs and tissues. We now know that chronic or uncontrolled inflammation is responsible for more than just autoimmune disease. In fact, it underlies the most fatal human diseases, including heart disease, Alzheimer’s disease, and even some forms of cancer.
These complex and often debilitating illnesses require effective anti-inflammatory drugs. But, there’s just one problem: current anti-inflammatory drugs are, in many cases, inefficient or unsuccessful.
Non-steroidal anti-inflammatory drugs (NSAIDs), like aspirin, are mainly used to treat low-level inflammation and reduce pain or swelling. Steroidal anti-inflammatory drugs called glucocorticoids are more powerful and have the ability treat a wide array of inflammatory conditions. But, glucocorticoids – while effective – can severely suppress the immune system and induce an array of side effects in some patients, including bone loss and high blood pressure.
Thankfully, new progress in inflammation research has the potential to inspire a new class of drugs that could ultimately change the way we treat human disease.
During inflammation, white blood cells must exit the blood vessel in a process called diapedesis before they can subsequently enter organs or tissues. When diapedesis occurs in large excess in a specific area of the body – for example, the knee joint of someone with rheumatoid arthritis – it can result in tissue destruction. As tissue breaks down, more white blood cells exit the local blood vessels and flock to the inflamed area, thus establishing a vicious cycle of chronic inflammation and tissue damage that can lead to heart disease, cancer, and a host of other illnesses.
Think of your immune system as an army, where white blood cells play the role of soldiers. Chronic or unwanted inflammation is akin to a group of rogue soldiers firing their weapons wildly and wreaking havoc. To combat distinct types of unwanted inflammation, many physicians prescribe glucocorticoids, which have the ability to strip the entire army of its ammunition. In fact, many anti-inflammatories are designed to achieve the same effect. While this aids in reigning in the rogue soldiers, it also leaves the army (your immune system) at a considerable disadvantage in its defense against routine bacteria and viruses.
Alternatively, what if there was a way in which we could selectively disarm the rogue soldiers without affecting the army as a whole? In other words, how can we treat inflammation in one area of the body without leaving other areas vulnerable to infection? This might be achieved by targeting endothelial cells, the cells that line the inside of blood vessels. These cells act as a type of “army general” of our immune system, controlling where and when white blood cells can exit the blood vessel during inflammation.
Similar to actual soldiers and generals, white blood cells and endothelial cells communicate with each other. When a white blood cell prepares to undergo diapedesis and exit the blood vessel during inflammation, it participates in a molecular handshake with endothelial cells by exchanging information about its motives and objectives. Once the proper signals are received, endothelial cells permit the white blood cell to exit the blood vessel, akin to a general granting a soldier permission to advance to the battlefield. Theoretically, inhibiting diapedesis by disrupting or altering the communication between endothelial cells and white blood cells in a specific area of the body would be an ideal approach to treat unwanted inflammation.
There are several labs around the world investigating endothelial cells and their role in diapedesis, including right here at Northwestern University. Dr. William Muller, who currently serves as the Department of Pathology Chairman at Feinberg School of Medicine, has had a long and impactful career studying how immune cells leave the bloodstream during inflammation. In fact, he is credited with the discovery of PECAM, the first known molecule on endothelial cells that regulates diapedesis. PECAM, which coats the outside of endothelial cells, works by directly interacting with PECAM on a white blood cell in a handshake-like manner. Once this interaction occurs, endothelial cells facilitate the white blood cell’s exit from the blood vessel.
Currently, Dr. Muller’s lab is focusing on identifying and understanding other molecules on endothelial cells, such as CD99 and VE-Cadherin, that participate in diapedesis. By illuminating how these molecules function in the context of inflammation, his lab hopes to uncover targets that could lead to better, more selective anti-inflammatory drugs.
Considerable progress has already been made in utilizing diapedesis as a point of intervention. A drug designed to treat multiple sclerosis called Natalizumab acts on a subset of white blood cells to prevent them from exiting the bloodstream and entering the brain and spinal cord where they can promote disease. Despite numerous risks and side effects, this therapy represents a shift in mentality in the field of anti-inflammatory therapeutics from a “sledgehammer”, or generalized approach, to one that is more defined.
Tyler Campbell, once a budding football star, did not play in the NFL. In fact, he was forced to quit the sport altogether due to MS therapies that failed to completely halt the destructive inflammation in his central nervous system. Fortunately, an expanded understanding of inflammation and its complexities is beginning to have an effect on the efficacy and selectivity of anti-inflammatory drugs. With continued diapedesis research by scientists like Dr. Muller, we may one day utilize a new class of anti-inflammatory therapeutics that could prevent cancer progression or treat rheumatoid arthritis without risking other medical complications. But in order to reach that point, researchers and doctors must distance themselves from the proverbial therapeutic “sledgehammer” and take a more careful, precise approach.